UPIT: Unleash the Potential of Intestinal Transplantation

UPIT：释放肠移植的潜力

• 批准号: 9919501
• 负责人: Alexander Helmut Kurt Kroemer
• 金额: $ 47.99万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-05 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919501
• 关键词: Adaptive Immune System; Address; Adoptive Transfer; Allografting; American; Antigens; B-Lymphocytes; Cells; Child; Complex; Country; Data; Epithelial; Epithelium; Failure; Foundations; Future; Goals; Grant; Home environment; Human; Immune; Immune response; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Inflammatory; Innate Immune System; Interleukin-17; Intestines; Knowledge; Lead; Life; Light; Lymphoid; Lymphoid Cell; Mediating; Morbidity - disease rate; Organ; Organ Transplantation; Outcome; Patients; Play; Prevention; Prevention approach; Procedures; Public Health; Quality of life; Regimen; Regulatory T-Lymphocyte; Research; Risk; Risk Factors; Role; Signal Transduction; Solid; System; T cell response; T-Cell Receptor; T-Lymphocyte; Therapeutic; Total Parenteral Nutrition; Transplant Recipients; Transplantation; Treatment Cost; United States; Work; adaptive immune response; allograft rejection; antimicrobial; base; cell type; cost; effector T cell; gastrointestinal transplantation; high risk; improved outcome; in vivo; innovation; insight; microbial; mortality; novel; novel therapeutics; preservation; prevent; response; sensor; side effect; transplant centers

Abstract Intestinal transplantation (ITx) has emerged as a key, but under-utilized and under-studied, therapeutic option for patients suffering from intestinal failure. Specifically, while an estimated 40,000 patients could benefit from ITx, a mere 141 ITx transplants were performed in the United States in 2015; the country's lowest volume solid organ transplant. This low volume is due to poor patient and allograft survival after ITx when compared to other fields of solid organ transplantation as this transplant is associated with the transplantation of the largest immune cell and microbial load of any solid organ. Because there is a high risk of allograft enteropathy/ immunological graft loss, strong regimens of generalized immunosuppression are typically applied, which lead to high morbidity and mortality. The result is a catch-22: if ITx is performed, the risk of rejection is high, which leads to over-immunosuppression, which results in complications and high treatment costs, which dissuades ITx from being offered in the first place. To untangle this catch-22 and unleash the potential of ITx, this project will leverage the fact that we are the leading ITx center in the country and lay the groundwork for a targeted immunotherapy approach to prevent/ control allograft enteropathy with minimization of generalized immunosuppression. Preliminary data has revealed that both the adaptive and innate immune systems are key players in stable allograft function and allograft enteropathy and as such, this project's three specific aims will focus on both systems: 1. To determine the roles and mechanisms of proinflammatory Th17 and protective regulatory T cell (Treg) responses in human ITx recipients with stable allograft function versus enteropathy 2. To determine the roles and mechanisms of proinflammatory type 1 innate lymphoid cell (ILC1) and protective type 3 innate lymphoid cell (ILC3) responses in human ITx recipients with stable allograft function versus enteropathy 3. To elucidate the crosstalk between the master regulators NOD2 (antimicrobial sensor) and CD39 (purinergic signaling) and innate and adaptive immune responses in human ITx recipients with stable allograft function versus enteropathy These three aims will lay the foundation for improving outcomes and quality of life for several patient groups: (A) patients who are on home-based TPN regimens could be considered for ITx, ideally before complications worsen that jeopardize the outcomes of ITx; (B) new and past recipients of ITx could avoid the life threatening complications from generalized immunosuppression, which will be especially beneficial for children who receive ITx in their earliest years of life; and (C) patients suffering from IBD could benefit from new therapeutic insights as we hypothesize that IBD is influenced by similar factors that modulate ITx enteropathy.

摘要 肠移植(ITX)已成为一种关键的治疗方法，但尚未得到充分利用和研究。 适用于肠衰竭患者。具体地说，虽然估计有40,000名患者可以受益于 2015年，美国仅进行了141例ITX移植；这是美国数量最低的 器官移植。这种低容量是由于ITX后患者和同种异体移植物的存活率较低 作为实体器官移植领域中与这种移植相关的最大的移植 任何固体器官的免疫细胞和微生物负荷。因为移植物肠病的风险很高。 免疫性移植物丢失，通常采用全身免疫抑制的强方案，这会导致 高发病率和高死亡率。结果是一个两难境地：如果进行ITX，排斥的风险很高，这 导致过度免疫抑制，从而导致并发症和高昂的治疗费用，这阻碍了 ITX从一开始就不被提供。 为了解决这一难题并释放ITX的潜力，这个项目将利用我们是 在全国领先的ITX中心，并为有针对性的免疫疗法方法奠定基础，以预防/ 控制同种异体移植肠病，尽量减少全身性免疫抑制。初步数据显示 研究表明，适应性免疫系统和先天免疫系统都是稳定的同种异体移植功能和 因此，该项目的三个具体目标将集中在这两个系统上： 1.探讨促炎性Th17和保护性调节性T细胞的作用及机制 同种异体移植功能稳定的人ITX受体对肠病的(Treg)反应 2.确定促炎性1型固有淋巴样细胞(ILC1)的作用和机制 稳定的人ITX受者的保护性3型固有淋巴样细胞(ILC3)反应 同种异体移植功能与肠病 3.阐明主调控子NOD2(抗菌传感器)与CD39之间的串扰 (嘌呤能信号)与先天和获得性免疫反应 稳定的同种异体移植功能对抗肠病 这三个目标将为改善几个患者群体的预后和生活质量奠定基础： (A)接受以家庭为基础的TPN方案的患者可以考虑接受ITX，最好是在出现并发症之前。 恶化，危及ITX的结果；(B)新的和过去的ITX接受者可以避免生命 全身性免疫抑制的危险并发症，这对儿童尤其有益 (C)患有IBD的患者可以受益于新的 我们假设IBD受到调节ITX肠病的类似因素的影响。